(-)-Galanthamine (and related compounds) are useful compounds for the treatment of Alzheimer's disease and related illnesses. Currently galanthamine is usually obtained by extraction from particular types of bulbs, such as daffodils or snowdrops.
It is known that single enantiomer galanthamine (2) can be prepared from racemic narwedine (1) through resolution followed by reduction of the enone function, as depicted in Scheme 1, below. Usefully, since the enantiomers of narwedine (1) readily equilibrate (racemise) by way of reversible ring opening to a dienone, coupled to the fact that crystals of racemic (1) exist as a conglomerate of enantiomers, a dynamic resolution of (1) can be carried out by crystallisation with entrainment by crystals of the desired isomer (see Barton and Kirby, J. Chem. Soc. (C) (1962) 806). However, in respect of a total synthesis, racemic narwedine itself is not readily available.
Numerous processes have been based on the biomimetic approach pioneered by Barton and Kirby in 1962, in which the key oxidative cyclisation step proceeded in only 1.4% yield. In later studies it was found that the yields of the phenolic coupling could be increased substantially by deactivation of the basic amine as either an amide or sulphonamide group, and by blocking the para-position with a removable group (i.e. replaceable by hydrogen) such as bromine, e.g. as in compound (3) in Scheme 2 below; see for instance Franck and Lubs, Liebigs. Ann. Chem. (1968) 720: 131; Kametani et al., J. Chem. Soc., Chem. Comm. (1969) 425 and J. Chem. Soc.(C) (1969) 2602-2605 and Szewczyk et al., J. Heterocyclic Chem. (1988) 1809).
However, processes operating on this strategy are cumbersome owing to the need to remove the amine protecting group from the product of the phenolic coupling (compound (4) in Scheme 2) by reduction. This invariably leads to concomitant reduction of the narwedine carbonyl group, and possibly other functional groups, producing racemic galanthamine and/or epigalanthamine, or derivatives thereof, as depicted by compound (5) in Scheme 2. To obtain racemic narwedine (1) from the latter compounds then requires a separate reoxidation step.